Estimating the hepatotoxic impact of hexavalent chromium on Ctenopharyngodon idellus through a multi-biomarker study

Abdel-Moneim, 2016, Biochemical and histopathological changes in liver of the Nile tilapia from Egyptian polluted lakes, Toxicol. Ind. Health, 32, 457, 10.1177/0748233713503374 Abdel-Warith, 2011, Effect of zinc toxicity on liver histology of Nile tilapia, Oreochromis niloticus, Sci. Res. Essays, 6, 3760, 10.5897/SRE11.883 Ahmed, 2013, Chromium (VI) induced acute toxicity and genotoxicity in freshwater stinging catfish, Heteropneustes fossilis, Ecotoxicol. Environ. Saf., 92, 64, 10.1016/j.ecoenv.2013.02.008 Ahmed, 2014, Lead and cadmium-induced histopathological changes in gill, kidney and liver tissues of freshwater climbing perch Anabas testudineus (Bloch, 1792), Chem. Ecol., 30, 532, 10.1080/02757540.2014.889123 Aki, 2012, Cytoplasmic vacuolization during exposure to drugs and other substances, Cell Biol. Toxicol., 28, 125, 10.1007/s10565-012-9212-3 Al-Yousuf, 2000, Trace metals in liver, skin and muscle of Lethrinus lentjan fish species in relation to body length and sex, Sci. Total Environ., 256, 87, 10.1016/S0048-9697(99)00363-0 Anavi, 2015, Steatosis-induced proteins adducts with lipid peroxidation products and nuclear electrophilic stress in hepatocytes, Redox Biol, 4, 158, 10.1016/j.redox.2014.12.009 Atli, 2008, Responses of metallothionein and reduced glutathione in a freshwater fish Oreochromis niloticus following metal exposures, Environ. Toxicol. Pharmacol., 25, 33, 10.1016/j.etap.2007.08.007 2017 Awasthi, 2018, An in vivo analysis of Cr6+ induced biochemical, genotoxicological and transcriptional profiling of genes related to oxidative stress, DNA damage and apoptosis in liver of fish, Channa punctatus (Bloch, 1793), Aquat. Toxicol., 200, 158, 10.1016/j.aquatox.2018.05.001 Bakshi, 2018, A comprehensive review on chromium induced alterations in fresh water fish, Toxicol. Reports, 5, 440, 10.1016/j.toxrep.2018.03.007 Barceloux, 1999, Chromium, J. Toxicol. Clin. Toxicol., 37, 173, 10.1081/CLT-100102418 Barilli, 2014, Oxidative stress induced by copper and iron complexes with 8-hydroxyquinoline derivatives causes paraptotic death of HeLa cancer cells, Mol. Pharm., 11, 1151, 10.1021/mp400592n Bautista, 2002, Neutrophilic infiltration in alcoholic hepatitis, Alcohol, 27, 17, 10.1016/S0741-8329(02)00206-9 Beg, 2008, Chemical contaminants and toxicity of Ganga river sediments from up and down stream area at Kanpur, Am. J. Environ. Sci., 4, 362, 10.3844/ajessp.2008.362.366 Benze, 2014, Subchronic exposure to diflubenzuron causes health disorders in Neotropical freshwater fish, Prochilodus lineatus, Environ. Toxicol., 31, 533, 10.1002/tox.22065 Beuge, 1978, Microsomal lipid peroxidation, Methods Enzymol, 52, 302, 10.1016/S0076-6879(78)52032-6 Beutler, 1963, Improved method of determination of blood glutathione, J. Lab. Clin. Med., 61, 351 Bhatkar, 2011, Chromium, nickel and zinc induced histopathological alterations in the liver of Indian common carp Labeo rohita (Ham.), J. Appl. Sci. Environ. Manag., 331 Braunbeck, 1993, Toxicant-induced cytological alterations in fish liver as biomarkers of environmental pollution? A case study on hepatocellular effects of dinitro-o-cresol in golden ide (Leuciscus idus melanotus), 55 Brunagel, 2002, Nuclear matrix protein alterations associated with colon cancer metastasis to the liver, Clin. Cancer Res., 8, 3039 Buters, 2017, Chromium(VI) contact dermatitis: getting closer to understanding the underlying mechanisms of toxicity and sensitization!, J. Invest. Dermatol., 137, 274, 10.1016/j.jid.2016.11.015 Cai, 2006, Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy, J. Am. Coll. Cardiol., 48, 1688, 10.1016/j.jacc.2006.07.022 Camargo, 2007, Histopathology of gills, kidney and liver of a Neotropical fish caged in an urban stream, Neotrop. Ichthyol., 5, 327, 10.1590/S1679-62252007000300013 Cao, 2011, Tissue-specific accumulation of cadmium and its effects on antioxidative responses in Japanese flounder juveniles, Environ. Toxicol. Pharmacol., 33, 16, 10.1016/j.etap.2011.10.003 Cengiz, 2006, Sublethal effects of commercial deltamethrin on the structure of the gill, liver and gut tissues of mosquitofish, Gambusia affinis: a microscopic study, Environ. Toxicol. Pharmacol., 21, 246, 10.1016/j.etap.2005.08.005 Charoensuk, 2014, Bile canalicular changes and defective bile secretion in Opisthorchis viverrini-infected hamsters, Folia Parasitologica, 61, 512, 10.14411/fp.2014.063 Chen, 2016, Accumulation and effects of Cr(VI) in Japanese medaka (Oryzias latipes) during chronic dissolved and dietary exposures, Aquat. Toxicol., 176, 208, 10.1016/j.aquatox.2016.05.002 Chen, 2014, Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes, J. Biol. Chem., 289, 22413, 10.1074/jbc.M114.548677 Cohen, 1993, Mechanisms of chromium carcinogenicity and toxicity, Crit. Rev. Toxicol., 23, 255, 10.3109/10408449309105012 Coyle, 2002, Metallothionein: the multipurpose protein, Cell. Mol. Life Sci., 59, 627, 10.1007/s00018-002-8454-2 CPCB (Central Pollution Control Board), 1997. Report on groundwater quality in Kanpur, status, sources and control measures: GWQS/8/1996-97. Central Pollution Control Board, India, 1, 4-5. CPCB (Central Pollution Control Board), 2021. Report of the joint committee as per order dated 21.01.2021 & 03.02.2021 in the matter of OA No. 186/2020. Submitted to Hon'ble National Green Tribunal Southern Branch Chennai. https://greentribunal.gov.in/sites/default/files/news_updates/Joint%20Committee%20Report%20in%20OA%20No%20186%20of%202020(SZ).pdf. Crawford, 2018, Structure, function and responses to injury, 1 Curello, 1985, Changes in the cardiac glutathione status after ischemia and repurfusion, Experientia, 41, 42, 10.1007/BF02005863 Das, 2015, Hexavalent chromium induces apoptosis in human liver (HepG2) cells via redox imbalance, Toxicol. Rep., 2, 600, 10.1016/j.toxrep.2015.03.013 Dillon, 1997, Microprobe X-ray absorption spectroscopic determination of the oxidation state of intracellular chromium following exposure of V79 Chinese hamster lung cells to genotoxic chromium complexes, Chem. Res. Toxicol., 10, 533, 10.1021/tx970010m Dubey, 2010, Transcriptomic and metabolomic shifts in rice roots in response to Cr(VI) stress, BMC Genomics, 11, 648, 10.1186/1471-2164-11-648 Espinoza, 2012, Effect of cadmium on glutathione S-transferase and metallothionein gene expression in coho salmon liver, gill and olfactory tissues, Aquat. Toxicol., 110-111, 37, 10.1016/j.aquatox.2011.12.012 Fang, 2018, Molecular cloning and functional analysis of growth arrest and DNA damage-inducible 45 aa and ab (Gadd45aa and Gadd45ab) in Ctenopharyngodon idella, Fish Shellfish Immunol, 77, 187, 10.1016/j.fsi.2018.03.051 Figueiredo-Fernandes, 2007, Histopathological changes in the liver and gill epithelium of Nile tilapia, Oreochromis niloticus, exposed to waterborne copper, Pesq. Vet. Bras., 27, 103, 10.1590/S0100-736X2007000300004 Flores-Toro, 2016, Autophagy in the liver: cell's cannibalism and beyond, Arch. Pharm. Res., 39, 1050, 10.1007/s12272-016-0807-8 Fricke, 2012, Liver histopathology in Baltic eelpout (Zoarces viviparus)-a baseline study for use in marine environmental monitoring, Marine Environ. Res., 82, 1, 10.1016/j.marenvres.2012.08.012 Galluzzi, 2017, Heavy metals to rock the immune infiltrate, Trends Immunol, 38, 539, 10.1016/j.it.2017.05.007 Galus, 2013, Chronic, low concentration exposure to pharmaceuticals impacts multiple organ systems in zebrafish, Aquat. Toxicol., 132-133, 200, 10.1016/j.aquatox.2012.12.021 Garcia-Nino, 2015, Oxidative stress markers and histological analysis in diverse organs from rats treated with the hepatotoxic dose of Cr(VI): effect of curcumin, Biol. Trace Elem. Res., 167, 130, 10.1007/s12011-015-0283-x Gauglhofer, 1991, Chromium, 853 Ge, 2019, Cr (VI) induces crosstalk between apoptosis and autophagy through endoplasmic reticulum stress in A549 cells, Chem. Biol. Inter., 298, 35, 10.1016/j.cbi.2018.10.024 Ghadially, 1988, 612 Gunaratnam, 2001, The interaction of the orthopaedic metals, chromium VI and nickel, with hepatocytes, J. Mater. Sci. Mater. Med., 12, 945, 10.1023/A:1012848729592 Gwaltney-Brant, 2016, Nutraceuticals in hepatic diseases, 87 Habig, 1974, Glutathione S-transferases. First enzymatic step in mercapturic acid formation, J. Biol. Chem., 249, 7130, 10.1016/S0021-9258(19)42083-8 Halder, 2017, Effect of chromium on glutathione-s-transferase and catalase activity and their respective gene expression in the brain tissue of F1 generation mice following prenatal exposure: modulation by quercetin, J. Clin. Toxicol., 7 Haschek, 2010, 197 Heath, 1995, 384 Henics, 1999, Cytoplasmic vacuolation, adaptation and cell death: a view on new perspectives and features, Biol. Cell, 91, 485, 10.1016/S0248-4900(00)88205-2 Hinton, 2008, Liver toxicity, 328 Hu, 2005, Golgi fragmentation is associated with ceramide-induced cellular effects, Mol. Biol. Cell., 16, 1555, 10.1091/mbc.e04-07-0594 2018 Ilias, 2011, Isolation and characterization of chromium (VI)-reducing bacteria from tannery effluents, Indian J. Microbiol., 51, 76, 10.1007/s12088-011-0095-4 Jaishankar, 2014, Toxicity, mechanism and health effects of some heavy metals, Interdiscip. Toxicol., 7, 60, 10.2478/intox-2014-0009 Jindal, 2019, Hexavalent chromium-induced toxic effects on the antioxidant levels, histopathological alterations and expression of Nrf2 and MT2 genes in the branchial tissue of Ctenopharyngodon idellus, Chemosphere, 230, 144, 10.1016/j.chemosphere.2019.05.027 Johnson, 2016, Revelation of molecular basis for chromium toxicity by phenotypes of Saccharomyces cerevisiae gene deletion mutants, Metallomics, 8, 542, 10.1039/C6MT00039H Kart, 2016, The therapeutic role of glutathione in oxidative stress and oxidative DNA damage caused by hexavalent chromium, Biol. Trace Elem. Res., 174, 387, 10.1007/s12011-016-0733-0 Keservani, 2015, Pulmonary and respiratory health: antioxidants and nutraceticals, 279 Kim, 2016, The chromium accumulation and its physiological effects in juvenile rockfish, Sebastes schlegelii, exposed to different levels of dietary chromium (Cr6+) concentrations, Environ. Toxicol. Pharmacol., 41, 152, 10.1016/j.etap.2015.12.001 Kim, 2017, Nrf2: A key regulator of redox signaling in liver diseases, 355 Knolle, 2001, Neighbourhood politics: the immunoregulatory function of organ-resident liver endothelial cells, Trends Immunol, 22, 432, 10.1016/S1471-4906(01)01957-3 Kono, 1978, Generation of superoxide radical during auto-oxidation of hydroxylamine and an assay for superoxide dismutase, Arch. Biochem. Biophys., 186, 189, 10.1016/0003-9861(78)90479-4 Kostaropoulos, 2005, Effects of exposure to a mixture of cadmium and chromium on detoxification enzyme (GST, P450-MO) activities in the frog Rana ridibunda, Ecotoxicology, 14, 439, 10.1007/s10646-004-1349-2 Kuykendall, 2006, Waterborne and dietary hexavalent chromium exposure causes DNA-protein crosslink (DPX) formation in erythrocytes of largemouth bass (Micropterus salmoides), Aquat. Toxicol., 78, 27, 10.1016/j.aquatox.2006.01.019 Lalor, 2002, Recruitment of lymphocytes to the human liver, Immunol. Cell Biol., 80, 52, 10.1046/j.1440-1711.2002.01062.x Lee, 2005, Nrf2, a multi-organ protector?, FASEB J, 19, 1061, 10.1096/fj.04-2591hyp Lena, 2010, The silencing of adenine nucleotide translocase isoform 1 induces oxidative stress and programmed cell death in ADF human glioblastoma cells, FEBS J, 277, 2853, 10.1111/j.1742-4658.2010.07702.x Liebel, 2013, Fish histopathology as biomarker to evaluate water quality, Ecotoxicol. Environ. Contam., 8, 9 Liebermann, 2008, Gadd45 in stress signaling, J. Mol. Signal., 3, 15, 10.1186/1750-2187-3-15 Lionetti, 2014, High-lard and high-fish-oil diets differ in their effects on function and dynamic behaviour of rat hepatic mitochondria, PLoS One, 9, e92753, 10.1371/journal.pone.0092753 Livak, 2001, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method, Methods, 25, 402, 10.1006/meth.2001.1262 Luck, 1971, 885 Lunardelli, 2018, Chromium accumulation and biomarker responses in the Neotropical fish Prochilodus lineatus caged in a river under the influence of tannery activities, Ecotoxicol. Environ. Saf., 153, 188, 10.1016/j.ecoenv.2018.02.023 Lushchak, 2008, The effect of potassium dichromate on free radical processes in goldfish: possible protective role of glutathione, Aquat. Toxicol., 87, 108, 10.1016/j.aquatox.2008.01.007 Marceau, 2012, Cation trapping by cellular acidic compartments: beyond the concept of lysosomotropic drugs, Toxicol. Appl. Pharmacol., 259, 1, 10.1016/j.taap.2011.12.004 Masella, 2005, Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes, J. Nutr. Biochem., 16, 577, 10.1016/j.jnutbio.2005.05.013 Merola, 2019, Materials for hip protheses: a review of wear and loading considerations, Materials (Basel), 12, 495, 10.3390/ma12030495 Miguel, 2011, Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease, Am. J. Physiol. Renal Physiol., 300, F734, 10.1152/ajprenal.00454.2010 Min, 2016, Bioaccumulation, alterations of metallothionein, and antioxidant enzymes in the mullet Mugil cephalus exposed to hexavalent chromium, Fish. Aqua. Sci., 19 Mishra, 2009, Chronic exposure to sublethal hexavalent chromium affects organ histopathology and serum cortisol of a teleost, Channa punctatus (Bloch), Sci. Total Environ., 407, 5031, 10.1016/j.scitotenv.2009.05.042 Misra, 2005, Immobilization of heavy metals in contaminated soil using nonhumus-humus soil and hydroxyapatite, Bull. Environ. Contam. Toxicol., 74, 725, 10.1007/s00128-005-0642-y Monteiro, 2018, Mutagenic and histopathological effects of hexavalent chromium in tadpoles of Lithobates catesbeianus (Shaw, 1802) (Anura, Ranidae), Ecotoxicol. Environ. Saf., 163, 400, 10.1016/j.ecoenv.2018.07.083 Morris, 1979, Lysosomal control in neurosecretion: the roles of cellular compartmentation and granular age, Biol. Cell, 36, 193 Myers, 1987, Pathologic anatomy and patterns of occurrence of hepatic neoplasms, putative preneoplastic lesions and other idiopathic hepatic conditions in English sole (Parophzys vetulus) from Puget Sound, Washington, USA, J. Natl. Cancer Inst., 78, 333 Nayak, 1996, The nature and significance of liver cell vacuolation following hepatocellular injury-an analysis based on observations on rats rendered tolerant to hepatotoxic damage, Virchows Arch, 428, 353, 10.1007/BF00202202 Nayak, 2020, A review of chromite mining in Sukinda valley of India: Impact and potential remediation measures, Int. J. Phytorem., 22, 804, 10.1080/15226514.2020.1717432 Nguyen, 2005, Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1, J. Biol. Chem., 280, 32485, 10.1074/jbc.M503074200 Nithyananthan, 2019, Chemotherapeutic doses of arsenic trioxide delays hepatic regeneration by oxidative stress and hepatocyte apoptosis in partial hepatectomy rat, Toxicol. Appl. Pharmacol., 114760 NTP (National Toxicology Program), 2008. Hexavalent chromium. nih.gov/results/areas/hexchrom/index.html. Opperman, 2008, A novel chromate reductase from Thermus scotoductus SA-01 related to old yellow enzyme, J. Bacteriol., 190, 3076, 10.1128/JB.01766-07 Patlolla, 2009, Potassium dichromate induced cytotoxicity, genotoxicity and oxidative stress in human liver carcinoma (HepG2) cells, Int. J. Environ. Res. Public Health, 6, 643, 10.3390/ijerph6020643 Peng, 1997, Polychlorinated biphenyl congener 153-induced ultrastructural alterations in rat liver: a quantitative study, Toxicology, 120, 171, 10.1016/S0300-483X(97)03663-9 Poleksic, 1994, Fish gills as a monitor of sublethal and chronic effects of pollution, 339 Poonia, 2021, Contamination of arsenic, chromium and fluoride in the Indian groundwater: a review, meta-analysis and cancer risk assessment, Int. J. Environ. Sci. Tech., 10.1007/s13762-020-03043-x Prasad, 2008, 30 Qi, 2000, Chromium(III)-induced 8-hydroxydeoxyguanosine in DNA and its reduction by antioxidants: comparative effects of melatonin, ascorbate, and vitamin E, Environ. Health Perspect., 108, 399, 10.1289/ehp.00108399 Rana, 2015, Histopathological study of liver and kidney in common carp (Cyprinus carpio) exposed to different doses of potassium dichromate, Int. J. Biosci., 6, 108 Rodrigues, 2010, Deleterious effects of water-soluble fraction of petroleum, diesel and gasoline on marine pejerrey Odontesthes argentinensis larvae, Sci. Total Environ., 408, 2054, 10.1016/j.scitotenv.2010.01.063 Rogers-Cotrone, 2010, Vacuolation of sensory ganglion neuron cytoplasm in rats with long-term exposure to organophosphates, Toxicol. Pathol., 38, 554, 10.1177/0192623310369343 Rowat, 2008, Towards an integrated understanding of the structure and mechanics of the cell nucleus, BioEssays News Reviews Mol. Cell Dev. Biol., 30, 226, 10.1002/bies.20720 Saadeh, 2007, Nonalcoholic fatty liver disease and obesity, Nutr. Clin. Pract., 22, 1, 10.1177/011542650702200101 Schaffener, 2010, Enhanced bioremediation pilot study of a Cr (VI)-impacted overburden groundwater system in Kanpur, Uttar Pradesh, India, Proceedings of the Annual International Conference on Soils, Sediments, Water and Energy, 13, 1 Sedman, 2006, Review of the evidence regarding the carcinogenicity of hexavalent chromium in drinking water, J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev., 24, 155, 10.1080/10590500600614337 Sekine, 2006, Oxidative stress and Mrp2 internalization. Free Radic, Biol. Med., 40, 2166 Sharma, 2012, Groundwater contaminated with hexavalent chromium [Cr (VI)]: a health survey and clinical examination of community inhabitants (Kanpur, India), PLoS One, 7, e47877, 10.1371/journal.pone.0047877 Sharma, 2019, Appraisal of heavy metal contents in groundwater and associated health hazards posed to human population of Ropar wetland, Punjab, India and its environs, Chemosphere, 227, 179, 10.1016/j.chemosphere.2019.04.009 Singh, 2007, Effect of monothiol along with antioxidant against mercury-induced oxidative stress in rat, Indian J. Exp. Biol., 45, 1037 Smedsrod, 2004, Clearance function of scavenger endothelial cells, Comp. Hepatol., 3, S22, 10.1186/1476-5926-2-S1-S22 Smith, 2015, General chemistry, sampling, analytical methods, and speciation, 15 Soudani, 2011, Effects of selenium on chromium (VI)-induced hepatotoxicity in adult rats, Exp. Toxicol. Pathol., 63, 541, 10.1016/j.etp.2010.04.005 Taguchi, 2011, Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution, Genes Cells, 16, 123e140, 10.1111/j.1365-2443.2010.01473.x Tanase, 2012, Apoptosis, 45 Tassi, 2018, Evidence for the natural origins of anomalously high chromium levels in soils of the Cecina valley (Italy), Environ. Sci., 20, 965 2010, 53 Trabbic, 2014, Differential induction of cytoplasmic vacuolization and methuosis by novel 2-Indolyl-substituted pyridinylpropenones, ACS Med. Chem. Lett., 5, 73, 10.1021/ml4003925 Tripathi, 2014, Transformed yeast (Schizosaccharomyces pombe) overexpressing rice Tau class glutathione-S-transferase (OsGSTU30 and OsGSTU41) shows enhanced resistance to hexavalent chromium, Metallomics, 6, 1549, 10.1039/C4MT00083H Tripathi, 2020, Detection of chromium in surface and groundwater and its bio-absorption using bio-wastes and vermiculite, Eng. Sci. Tech. Int. J., 23, 1153 Velma, 2010, Chromium-induced biochemical, genotoxic and histopathologic effects in liver and kidney of goldfish, Carassius auratus, Mutat. Res., 698, 43, 10.1016/j.mrgentox.2010.03.014 Vutukuru, 2007, Effect of arsenic and chromium on the serum amino-transferases activity in Indian major carp, Labeo rohita, Int. J. Environ. Res. Public Health, 4, 224, 10.3390/ijerph2007030005 Wang, 2006, Oral administration of Cr(VI) induced oxidative stress, DNA damage and apoptotic cell death in mice, Toxicology, 228, 16, 10.1016/j.tox.2006.08.005 Wang, 2008, Acute trimethyl tin exposure induces oxidative stresses response and neuronal apoptosis in Sebastiscus marmoratus, Aquat. Toxicol., 90, 58, 10.1016/j.aquatox.2008.07.017 Waseem, 2014, Pollution status of Pakistan: a retrospective review on heavy metal contamination of water, soil, and vegetables, BioMed Res. Int., 10.1155/2014/813206 Webster, 2009, Sizing up the nucleus-nuclear shape, size and nuclear envelope assembly, J. Cell Sci., 122, 1477, 10.1242/jcs.037333 Wilson, 2010, The nuclear envelope at a glance, J. Cell Sci., 123, 1973, 10.1242/jcs.019042 Yang, 2014, Hepatic toxicity biomarkers, 241 Yang, 2009, Gadd45 proteins as critical signal transducers linking NF-κB to MAPK cascades, Curr. Cancer Drug Targets, 9, 915, 10.2174/156800909790192383 Yuan, 2017, Accumulation and detoxification dynamics of chromium and antioxidant responses in juvenile rare minnow, Gobiocypris rarus, Aquat. Toxicol., 190, 174, 10.1016/j.aquatox.2017.07.005 Zhitkovich, 2005, Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI), Chem. Res. Toxicol., 18, 3, 10.1021/tx049774+ Zhong, 2017, Mitochondrial biogenesis in response to chromium (VI) toxicity in human liver cells, Int. J. Mol. Sci., 18, 1877, 10.3390/ijms18091877 Zsembery, 2000, Bile formation: a concerted action of membrane transporters in hepatocytes and cholangiocytes, News Physiol. Sci., 15, 6